Gaucher Disease: New Expanded Classification Emphasizing Neurological Features.

Gaucher disease (GD) is a rare inherited metabolic disorder and the most common lysosomal storage disorder, caused by a deficiency in glucocerebrosidase enzyme activity. It has been classified according to the neurological manifestations into three types: type 1, without neuropathic findings, type 2 with acute infantile neuropathic signs and type 3 or chronic neuropathic form. However, report of new variants has led to the expansion of phenotype as a clinical phenotype of GD considered as a continuum of phenotypes. Therefore, it seems that a new classification is needed to cover new forms of the disease.


Introduction
Lysosomal storage disorders (LSDs) are a different group of nearly sixty inherited metabolic diseases (1) characterized by an accumulation of harmful products in the lysosomes because of malfunction of its specific proteins. As a result of a lysosomal dysfunction, cellular function disrupts and clinical abnormalities appear subsequently. In respect of the intracellular depository material, LSDs can be divided into three major groups including the sphingolipidoses, mucopolysaccharidoses, and glycoproteinoses (2).
Gaucher disease (GD, OMIM #230800, ORPHA355) is the most common sphingolipidoses (1,3) with an accumulation of the toxic amounts of certain fatty materials-glucosylceramide-primarily within the lysosomes of macrophages in the diverse tissues, transforming macrophages into storage cells named Gaucher cells throughout the body (4,5). by the visceral presentations without CNS involvement (18) distinguishing from the other two types in neuropathic group (19).

New insights to neuropathic variants
In fact, because any combination of the GD's types may occur in any individual patient, it is increasingly recognized that this classification is somewhat non practical (22). Recognition of a subset of patients with type I GD who developed PD (29) and peripheral neuropathies (30), has led to the expansion of phenotype as a clinical phenotype of GD to be considered as a continuum of phenotypes (31).
Therefore, it appears that classification of GD needs to be modified periodically as the new variants introduced. Accordingly, we revised current conventional classification to the new expanded classification based on literature (9, 15-17, 27, 30-40) (Figure 1).

Epidemiology
Nowadays, GD is classified in "orphan diseases" category, which comprises a group of rare disorders with prevalence of 1:50,000 or lower in the general population (1). The incidence of GD is 1 in 40,000 -60,000 to 100,000 births in the general population but it could reach up to 1 in 800 -1,000 in Ashkenazi Jewish populations (5,41).
GD affects men and women equally. According to a report by the National Organization for Rare Disorders, the GD incidence rate may be as high as   cases overall. In general, GD has an estimated frequency of 1 in 100,000 to 500,000 live births (46,47). Like other types of GD, type 2 GD is panethnic in occurrence (33). GD3: Type 3 GD is also a rare form that affects fewer than 1 in 100 000 people (26)(27)(28).

Genetic and inheritance pattern
GD is inherited in an autosomal recessive pattern which means both parents must be heterozygote carriers of a mutated gene for production of an affected zygote during conception.
In each pregnancy, the chance of fetus to have two (i. e., affected) or no (i. e., unaffected) mutated genes is 25%. Moreover, there is a 50% chance with each pregnancy that the offspring have a mutation from one of parents (i. e., heterozygote carrier). Heterozygote carriers typically do not reveal clinical features of the condition (46)(47)(48)(49).
GD is caused by the mutations in the glucocerebrosidase (GBA) gene on the first chromosome (1q21), composing of 11 exons and 10 introns with 7. 6 kb in length (23). Mutations in the GBA gene cause all three primary forms of GD by altering the stability of the glucosylceramidase or its active site. To date, more than 300 mutations have been described (50).

Pathophysiology and Neuropathogenesis
Glycosphingolipids (GSLs) are essential components of eukaryotic cell membranes synthesized in the endoplasmic reticulum and Golgi apparatus and degraded in the lysosomes. They are vital for life (7,51). Glucocerebrosidase also called glucosylceramidase (GlcCerase, GCase) or acid beta-glucosidase is the lysosomal hydrolase coded by the GBA gene (3)(4)(5). Glucocerebroside also known glucosylceramide (GlcCer) is the simplest GSL in the cell membrane of many organs that normally hydrolyzed into glucose and a simpler fat molecule called ceramide by GlcCerase (8,10). Any mutation in the GBA1 gene causes a diminished activity of GCase. Its deficiency, consequently lead to the accumulation of GlcCer in the lysosomes of macrophages, transforming them into storage cells called Gaucher cells ( Figure 2) and cellular dysfunction (52). The exact pathophysiological mechanisms of neurotoxicity are not understood (3) and it is probably different than those of systemic involvement (53). Gaucher cells are found in the brain of patients with neuronopathic GD associated with neuronal loss and glial activation (54,55).
Because the GlcCer turnover in neurons is low, its accumulation is considered significant only when residual GCase activity is notably diminished (56).
In the neuronopathic GD, Gaucher cells can be found in the perivascular regions and brain parenchyma. In the areas with neuronal loss of the type II GD, brain parenchyma involvement especially in cortical layers III and V, hippocampus brainstem and cerebellum is more frequently reported (54)(55)(56).
As mentioned in classification section, conventional and universally-accepted variants of GD include non-neuropathic (type 1 GD) form and neuropathic (type 2 GD and type 3 GD) forms (14-18).
The recognition of new atypical phenotypes with intermediate features and considering that even patients with type 1 GD can be present with some late-onset neurological presentations, has led to

1) Neurological manifestations
In Type 1 GD, the nervous system may be Although there are no primary neurological manifestations in type1GD, certain neurological presentations such as PD and peripheral neuropathy in association with this type have been reported in recent years (3,17). The frequency of PD (58)(59)(60) and symptomatic peripheral neuropathies (61) in type 1GD is higher than in the general population (57). The risk of developing PD in type 1 GD is 5%-7% and 9%-12% before the age 70 and 80 years, respectively (62). The life-time risk of developing PD is an approximately 26-fold higher than the general population (62,63), often at an earlier age (mean approximately 4-5 yr earlier) (59)(60)(61). Moreover, the risk of developing PD may  and mild cortical atrophy on brain MRI have been reported (76,83).

2) Non neurological manifestations
Affected newborns often appear normal at birth, but the disease manifests by 3 to 6 months (39,84).
Failure to thrive (30% of cases) may be the first sign makes parents to seek medical attention. It can progress to cachexia in the presence of insufficient nutritional intake (39). Splenomegaly (59% of cases) almost always is the most common finding detected in the onset of disease. Hypersplenism is associated with thrombocytopenia in 60% of cases with or without anemia and leukopenia, usually followed by hepatomegaly (39, 52).
Bone involvement is not seen in the type 2 GD, perhaps because there is no sufficient time for the skeletal system involvement (82). Interstitial lung disease occurs due to chronic aspiration, repeated respiratory infections and Gaucher cell infiltration (12,22,39,52). Repeated aspiration and/or prolonged and frequent apnea are the cause of 50% of deaths (23).

Perinatal-lethal (Fetal-Neonatal) subtype
The prevalence of this type is lower than one percent (86). It is the most severe form of GD (37).
The activity of residual GBA is almost zero (87).
The patients can present with either non-immune hydrops fetalis or neonatal ichthyosiform-collodion cutaneous abnormalities (85).
Perinatal-lethal GD with triad of "hydrops, ichthyosis, and fetal akinesia sequence" has been associated with specific severe mutations (87). Neurological presentations are a hallmark of type 3 GD (97).

1-1) Neuro-ophthalmic disorders
The earliest and most common findings are  (97,99). Therefore, ophthalmologists are often primary physicians that visit the patients and then suggest diagnosis of type 3 GD (100). The slowed horizontal saccadic eye movements occasionally are the only neurological symptom (12). Clinically detection of the saccade initiation failure may be difficult. However, it can be simply exposed as absent quick phases by inducing optokinetic and vestibular nystagmus (101). Besides, involvement of vertical saccades may occur (52).
Similar to type 2 GD (76,83,85), abnormal patterns can be seen in EEG including generalized background slowing or epileptiform discharges as the spike discharges (97,102). Some patients may present with myoclonic epilepsy without clinically significant visceral storage. Therefore, it can be concluded that GCase deficiency screening should be considered in patients with progressive myoclonic epilepsy in setting of unknown underlying etiology (52).

1-3) Cognition and intelligence disorders
Cognitive deficits have been reported in 33% of the patients (52). Cognitive impairments typically affect general nonverbal skills with relative sparing of verbal skills (12). As a result, the verbal IQ is typically more than the performance IQ, suggesting a visual-spatial deficits possibly secondary to oculomotor or other motor problems (103). Some patients present with IQ lower than average along with language difficulties, perceptual organization skills, and several learning and functional disabilities (12,97). Interestingly, patients can occasionally exhibit upper limit normal of IQ scale's ranges, especially high verbal IQ scores with success in the college and higher degrees (12,97,103).

1-4) Miscellaneous disorders
Behavioral changes, dementia and unexpected death are described in some patients (23). Developmental delay, hearing impairment and other brainstem deficits have been reported. Abnormal "brainstem auditory and somatosensory" evoked potentials have also been noted in some individuals (95).
Progressive kyphosis that may develop requiring spinal surgery (23). In the course of disease, progressive cerebellar ataxia or spasticity occur in about 20%-50% of patients affecting walking, and then standing (101).

2) Non neurological manifestations
Similar to type 2 GD, patients with type 3 GD can present with very aggressive visceral disease (104). Therefore, presentation with this phenotype at younger than 2 years of old is frequently associated with type 3 GD (22  (106).

Subtype 3a GD
Subtype 3a GD is characterized by mild visceral involvement, but with severe rapidly progressive neurological manifestations including oculomotor apraxia, cerebellar ataxia, spasticity, progressive myoclonic epilepsy refractory to treatment, and dementia (12,106). The prognosis is poor leading to death within the first two decades (13,102). The age of presentation as well as the rate of disease progression are variable (12).

Subtype 3c GD
Subtype 3c GD is an atypical rare variant (82) characterized by fatally progressive cardiac valves (tricuspid, mitral or aortic) and ascending aortic calcifications or fibrosis, supranuclear gaze palsy, mild hepatosplenomegaly, corneal opacities and bone disease and hydrocephalus and skeletal anomalies (5,12,13,27,52). This phenotype was first reported among Arab patients with GD from the Jenin area, but reported among other ethnic groups later (82). It is also exclusively associated with a complete genotype-phenotype correlation across several ethnicities with homozygosity for the D409H (G1342C) mutation (12,22,76).
Although subtype 3c presents with a unique phenotype, considerable clinical overlap exists between subtypes 3a and 3b (35). They often die in early adulthood (13).

Norrbottnian variant
The subtype 3 Norrbottnian GD is characterized by early onset massive visceral involvement, progressive kyphoscoliosis and mild cognitive deficits (76